Abstract
Shear-resistant arrest of circulating tumor cells is required for metastasis from the blood stream. Arrest during blood flow can be supported by tumor cell interaction with attached, activated platelets. This is mediated by tumor cell integrin alpha(v)beta3 and cross-linking plasma protein ligands. To analyze the mechanism of tumor cell ligand interactions under dynamic flow conditions, we used real-time video microscopy and tested human melanoma cell binding to fibrinogen, von Willebrand Factor, or fibronectin matrices in a buffer perfusion system. When perfused at venous flow, melanoma cells arrested abruptly and began to spread immediately. This was uniquely mediated by integrin alpha(v)beta3 on all tested ligands, and required alpha(v)beta3 activation and actin polymerization. Under static conditions, alpha(v)beta3 cooperated with alpha(v)beta1 and alpha5beta1 in supporting melanoma cell adhesion to fibronectin. But even when activated, beta1 integrins did not contribute to melanoma cell arrest during flow. Soluble ligand served as a cross-linker between attached and circulating tumor cells and enhanced melanoma cell arrest. Cohesion of activated melanoma cells was restricted to the matrix surface and did not occur in suspension. We conclude that the presence of alpha(v)beta3 in a functionally activated state provides a unique advantage for circulating tumor cells by promoting tumor cell arrest in the presence of flow-dependent shear forces.
Highlights
Metastasis to distant organs is a key characteristic of malignancy
Melanoma Cells Arrest on Immobilized Plasma Proteins under Dynamic Flow Conditions—We previously demonstrated that human tumor cells can attach to adherent, activated platelets during blood flow, and that plasma proteins are required for this interaction [5, 6]
To analyze the mechanism of tumor cell ligand binding during flow, we chose a buffer perfusion system and individual matrix proteins to reduce the complexity of possible cell-cell and cell-ligand interactions that can occur, when tumor cells are suspended in blood and allowed to stream past reactive surfaces
Summary
Metastasis to distant organs is a key characteristic of malignancy. This often involves the blood stream, where circulating tumor cells are exposed to flow-dependent shear forces that physically oppose tumor cell anchorage. To analyze the mechanism of tumor cell ligand interactions under dynamic flow conditions, we used real-time video microscopy and tested human melanoma cell binding to fibrinogen, von Willebrand Factor, or fibronectin matrices in a buffer perfusion system.
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